It is the intent of all sustained-release pharmaceutical preparations to provide a longer period of pharmacologic effect after the administration of a drug than is ordinarily experienced after the administration of immediate release preparations of the same drug. Such longer periods of efficacy can provide many inherent therapeutic benefits that are not achieved with corresponding immediate release preparations. The benefits of prolonged treatment of the nasal and non-nasal symptoms of seasonal allergic rhinitis or chronic idiopathic urticaria afforded by sustained release oral preparations have become universally recognized and oral sustained-release preparations are commercially available.
Another approach to sustained delivery of a therapeutically active agent is transdermal delivery systems, such as transdermal patches. Generally, transdermal patches contain a therapeutically active agent, a reservoir or matrix containing the active ingredient(s) and an adhesive which allows the transdermal device to adhere to the skin, allowing for the passage of the active agent from the device through the skin of the patient. Once the active agent has penetrated the skin layer, the drug is absorbed into the blood stream where it can exert a desired pharmacotherapeutic effect.
In spite of the known art related to transdermal therapy, there exists a need for the transdermal delivery of a beneficial agent for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria.
Loratadine, commercially available as Claritin® in the U.S. from Schering Corporation (Kenilworth, N.J. 07033, U.S.A.), is a long-acting tricyclic antihistamine with selective peripheral histamine H1-receptor antagonistic activity, with the chemical name, ethyl 4-(8-chloro-5,6-dihydro-11H-benzo cyclohepta pyridin-11-ylidene)-1-piperidinecarboxylate, and it is used mainly for treating nasal and non-nasal symptoms of seasonal allergic rhinitis, but may also be used in the treatment of chronic idiopathic urticaria, a common skin disorder . It is in the form of a white to off white powder, not soluble in water, but very soluble in organic solvents. Loratadine inhibits the activity of the substance, histamine, thus reducing the allergic effects caused by this substance such as itching, sneezing, runny nose and watery eyes. Loratadine is preferable to other antihistamines because it is nonsedating and does not cause cardiac arrhythmias brought on by use of some other antihistamines. The recommended oral dosage of loratadine for adults and children 12 years old or older is 10 mg once daily. In patients with liver or renal problems, the initial oral dosage of loratadine should be 10 mg every other day.
Seasonal allergic rhinitis (hay fever) is a term used to describe the symptoms caused seasonally by an allergic reaction that occurs in the eyes, nose, and throat in response to airborne allergens such as pollen from trees, grasses, and weeds. Other possible allergens include dust mites, molds, and animal dander. The allergens produce an allergic response by misleading the immune into thinking that the allergen is a harmful substance, thereby causing the immune system to produce antibodies to this specific allergen. When that allergen enters the immune system again, a reaction occurs between the allergen and IgE antibodies triggering the release of substances such as histamine from mast cells and other cells, producing symptoms such as runny nose, watery eyes, sneezing, and itching.
Chronic urticaria is an allergic skin disorder characterized by hives, e.g. red welts or small bumps, on the skin which are very itchy. Patients with chronic urticaria have hives that last longer than six months. This skin disorder is caused by an antigen-antibody reaction in which histamine and other substances such as acetyl choline are released from mast cells and other cells causing symptoms such as swelling, itching, pain, and rash. There are also cases in which there are no known causes for the hives (chronic idiopathic urticaria). As with chronic urticaria, antihistamines are used for treating chronic idiopathic urticaria.
Symptoms of seasonal allergic rhinitis and chronic idiopathic urticaria are improved by treatment with nonsedating antihistamines. Nonsedating antihistamines such as loratadine (The Merck Index, 11th Edition, Merck & Co., Inc., Rahway, N.J. U.S.A. 1989, hereby incorporated by reference) act as an antagonist to the peripheral histamine H1 receptor by selectively binding to this receptor, thereby blocking histamine from being released from the immune system and thus preventing histamines unwanted effects. (Goodman and Gillmans, The Pharmacological Basis of Therapeutics, 9th Edition, hereby incorporated by reference).
Following oral administration, loratadine is rapidly absorbed, fast acting, and undergoes extensive first pass metabolism to the active metabolite descarboethoxyloratadine. Food delays absorption, so loratadine should be taken on an empty stomach. Pharmacokinetic studies have revealed that the onset of antihistamine activity occurs within 1-3 hours following administration of loratadine, reaching a maximum at 8-12 hours and lasting in excess of 24 hours. There was no evidence of tolerance to this effect after 28 days of dosing with loratadine. After 10 days of dosing, a mean peak plasma concentration of 1.3 hours and 2.3 hours (Tmax) was observed in loratadine and the active metabolite, respectively. The mean elimination half-life observed in normal adults was 8.4 hours for loratadine and 28 hours for active metabolite. In patients with chronic liver disease, a mean half-life for loratadine and descarboethoxyloratadine of 24 hours and 37 hours were observed, respectively. Within 10 days of dosing, approximately 80% of the total loratadine administered were found in equal proportions between the urine and feces in the form of metabolic products. Finally, loratadine is 97% plasma-protein bound.
The most common adverse side effects of loratadine therapy include headache, somnolence, fatigue, and dry mouth. Less common or rare side effects may include altered lacrimination, altered salivation, flushing, hypoesthesia, impotence, increased sweating, thirst, angioneurotic edema, asthenia, back pain, blurred vision, chest pain, earache, eye pain, fever, leg cramps, malaise, rigors, tinnitus, viral infection, weight gain, hypertension, hypotension, palpitations, superventricular tachyarrhythmias, syncope, tachycardia, blepharospasm, dizziness, dysphonia, hypertonia, migraine, paresthesia, tremor, vertigo, altered taste, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastritis, hiccup, increased appetite, nausea, stomatitis, toothache, vomiting, arthraglia, myalgia, agitation, amnesia, anxiety, confusion, decreased libido, depression, impaired concentration, insomnia, irritability, paroniria, breast pain, dysmenorrhea, menorrhagia, vaginitis, bronchitis, bronchospasm, coughing, dyspnea, epistaxis, hemoptysis, laryngitis, nasal dryness, pharyngitis, sinusitis, sneezing, dermatitis, dry hair, dry skin, photosensitivity reaction, pruritis, purpura, rash, urticaria, altered micturition, urinary discoloration, urinary incontinence, urinary retention. Further, the following spontaneous adverse effects were rarely reported for loratadine: abnormal hepatic function, including jaundice, hepatitis, and hepatic necrosis, alopecia, anaphylaxis, breast enlargement, erythema multiforme, peripheral edema, and seizures. (Physicians' Desk Reference, 53rd Edition, 1999, hereby incorporated by reference).
Despite advances in the art, there remains a need for methods of treating patients with seasonal allergic rhinitis and chronic idiopathic urticaria with an agent that provides effective levels of loratadine for prolonged periods of time, preferably while eliminating or minimizing the symptoms of seasonal allergic rhinitis or chronic idiopathic urticaria, and/or any of the other above mentioned side effects, thus providing a safe and effective method of management of such allergic reactions and skin disorders.